This application requests funds to support a Mentored Quantitative Research Career Development Award (K25). The candidate has formal training in physics and imaging sciences, and seeks to become an independent investigator in the interdisciplinary field of cancer imaging. A career development plan has been established that includes critical didactic training, laboratory training, and other career development activites that ensure the candidate's transition to an independent investigator. The proposed didactic and laboratory trainings include cancer biology, biostatistics, multiple imaging modalities, clinical cancer imaging, and a progressive plan is proposed for the candidate to develop necessary skills as an independent investigator, including grant writing skills, mentoring skills, scientific reviews, and other topics related to research ethics. A mentor committee formed by established scientist from different fields will guide the candidate to develop an independent research group in the field of cancer research. The proposed research seeks to develop and validate advanced diffusion-weighted magnetic resonance imaging (DW-MRI) techniques using oscillating gradients (OGSE) for quantitative characterization of tumor pathophysiology, and to assess their role as potential non-invasive imaging biomarkers to monitor tumor early response to treatment. Currently, the conventional DW-MRI has been widely adapted in translational and clinical cancer studies to monitor variations in tumor cell density in order to assess therapeutic response. However, the cell density change in treated tumors is a downstream effect, reflecting a late tumor response to treatment. Capturing initial physiological variations within cells following treatment is a potentially earlier and more specific imaging biomarker that may be capable of predicting ultimate therapeutic outcomes. We therefore have developed a new OGSE technique capable of detecting intracellular microstructural variations, and hence capable of probing physiological states of cells. We aim to develop and validate the OGSE method as a potential imaging biomarker in cancer. To accomplish this, we will evaluate the OGSE method in three types of cancer treatment models, exhibiting distinct three classes of subcellular morphology following treatment before subsequent changes in cell density: 1) cells with multiple copies of DNA contents and organelles - polyploidy (>=8n); 2) doubled copies of DNA contents and organelles in M phase (4n); and 3) cells arrested in pre-apoptotic states - sub-G0 phase (2n). In particular, we will perform theoretical modeling (Aim I), in vitro cell culture studies (Am II) and in vivo animal imaging methods (Aim III) to comprehensively investigate the sensitivity and specificity of the OGSE method to specific intracellular microstructural variations following anti-cancer treatment. If successful, the methods described in this proposal would provide a new MR technique that is capable of providing specific assessment of tumor status non-invasively and predicting ultimate therapeutic outcomes at early stage of treatment.